Process and apparatus for making rapidly dissolving dosage units and product therefrom

ABSTRACT

The present invention is a method of preparing rapidly dissolving comestible units such as tablets. The present invention also includes an apparatus for making the comestible units and the units themselves. The product prepared in accordance with the present invention can include active ingredients and is capable of dissolving in the mouth of the consumer within several seconds. The unit dosage forms prepared in accordance with the present invention are particularly useful as antacids and as a delivery vehicle for biologically active ingredients, especially those which are ideally combined with antacid ingredients in order to ameliorate the effects of antacid environment.

The present application is a division of U.S. application Ser. No.08/652,252 filed on May 23, 1996 U.S. Pat. No. 5,622,719, which is acontinuation of U.S. application Ser. No. 08/259,496 filed on Jun. 14,1994, abandoned, which is a continuation-in-part application of U.S.application Ser. No. 08/133,669 filed Oct. 7, 1993 U.S. Pat. No.5,597,416, and a continuation-in-part of U.S. application Ser. No.08/119,974 filed Sep. 10, 1993, U.S. Pat. No. 5,518,551. Reference isalso made to co-pending commonly-owned U.S. application entitled"Process For Forming Quickly Dispersing Comestible Unit And ProductTherefrom," U.S. application Ser. No. 08/259,258 filed Jun. 14, 1994,the disclosure of which is incorporated herein.

BACKGROUND OF THE INVENTION

The present invention relates to the art of making comestible dosageunits, such as tablets, which dissolve rapidly in the mouth.

Dosage units in the form of tablets are usually prepared by compressinga formulation containing a medicinal substance or drug and otheringredients, such as excipients selected for properties which facilitateproduction and use of the tablet. There are currently three known basicmethods for preparing tablet granulations. These are wet granulation,dry granulation and direct compression. Both wet and dry granulationsinvolve the formation of an agglomerate for feeding to a die cavity.Direct compression usually involves compressing a powder blend of anactive ingredient with suitable excipients.

The preparation of formulations for tabletting by wet granulation is theoldest method and still the most widely used. Wet granulation involvesmany steps, including: milling of drugs and excipients, mixing of themilled powders, preparation of binder solution, mixing of bindersolution with powder mixture to form a wet mass, coarse screening of thewet mass using 6-12 mesh screens, drying of moist granules, screening ofdry granules through 14-20 mesh screen, mixing of screen granules withlubricant and disintegrant, and tablet compression.

Wet granulation is an expensive process because it requires manyprocessing steps and involves considerable material handling equipment.Consequently, the process requires both energy and substantial spacewhich should be environmentally controlled.

Dry granulation refers to the granulation of a powder mixture bycompression without the use of heat and solvent. Dry granulation is usedwhen wet granulation is not available because the drug is sensitive tomoisture or heat.

Two methods are used for dry granulation. One method is slugging, wherethe powder is precompressed on a heavy-duty tablet press, and theresulting tablets or slugs are milled to yield the granulation. Theother method is precompression of the powder with pressure rolls using acompactor.

Dry granulation has many disadvantages. It requires a specializedheavy-duty tablet press to form the slug; it does not permit uniformcolor distribution as can be achieved with wet granulation, where dyecan be incorporated into the binder liquid; the pressure roll presscannot be used with insoluble drugs because this may retard thedissolution rate; and the process tends to create dust therebyincreasing the potential for cross-contamination.

Direct compression tabletting has the least amount of steps. Directcompression is used in a process by which tablets are compresseddirectly from powder blends of the active ingredient and suitableexcipients (including fillers, disintegrants, and lubricants) which areincluded in the mix to provide uniform flow into the die cavity and forma firm solid compression tablet. No pretreatment of the powder blends bywet or dry granulation procedures is necessary.

Although it has considerably fewer steps than either wet or drygranulation processes, direct compression also has many technologicallimitations. These limitations include primarily obtaining sufficientflow, and obtaining bonding of particles to form a strong compressedtablet. Low-dose drugs are difficult to blend, that is, uniformdistribution of the drug is not easily attained and unblending sometimesoccurs during the compression stage. High-dose drugs do not lendthemselves to direct compression because of poor flowability and poorcompressibility. A typical example would be some of the antacid drugs,such as aluminum hydroxide and magnesium carbonate.

When direct compression is used the choice of excipients is extremelycritical. It is desirable that when using direct compression fillers andbinders possess both compressibility and fluidity. In addition tocompressibility failures, the process of direct compression also hasdisadvantages in the area of blending. Direct compression blends aresubject to unblending in post blending handling steps. Differences inparticle size because of differences in density between drug andexcipient particles may also lead to unblending in the hopper orfeedframe on the tablet press.

A disadvantage of all prior art process is the production of finesusually associated with making compression tablets. In the prior art,preparation of particles for formulation of tablets by compressionresults in a noticeable amount of fines, i.e., very tiny particles onthe order of 150 microns and less. These fines can interfere withoperation of apparatus for feeding tabletting machines as well as theoperation of the tabletting machines. Often, it is necessary to conducttablet production in a facility which is environmentally controlled toeliminate or reduce the fines. This adds to the cost of production ofthe tablets.

Moreover, a percentage of the non-compressed particulate is lost duringproduction because there are fines dispersed and cannot be recaptured,and because some of the fines are not capable of being recovered forrecycle.

In order to overcome the disadvantages associated with the prior art setforth above, technology has been developed by the common owner of thepresent application and co-pending U.S. parent application Ser. No.194,682 filed Feb. 10, 1994 U.S. Pat. No. 5,654,003. The commonly-ownedcase discloses a unique procedure in which compression tabletting can besimply and accurately manufactured by "fuse and compression" steps.Fusion is achieved by flash flow processing the tablet ingredients toprovide shearform matrix masses which are subsequently compressed toform comestible compression units. This process includes advantages ofwet and dry granulation and direct compression but does not have thedisadvantages associated with these prior art procedures.

Dr. Fuisz has several patents which relate to other unique deliverymeans. For example, in U.S. Pat. No. 4,855,326, Dr. Fuisz discloses afiber form of medicament-bearing product which can be compacted to forma sheet-like body. He cautions, however, that the compact body cannot besqueezed too much for fear of breaking the fibrous mass. There is noindication to form a compressed tablet as a medicinal dosage form.

Similarly, in U.S. Pat. No. 4,873,085 a spun fibrous cosmetic isdisclosed as well as a compacted form of sugar fibers to form asheet-like body which can be handled more readily. There is noindication to form a compressed tablet.

In U.S. Pat. No. 4,997,856, a wafer-like structure is disclosed in whicha medicament is distributed on or through spun fibers which are thenchopped by passing through a conventional "food grinder" (Hobarthamburger grinder). The enclosed volume of the end product is less than30%, and preferably less than 15%, of the as-spun volume of floss. Thereis no mention in the '856 disclosure to form a compressed tablet.

The use of compacted spun fibers in the same sense as in the patentsmentioned above is also disclosed in U.S. Pat. No. 5,034,421 and U.S.Pat. No. 5,096,492. None of these disclosures suggest formation of acompressed tablet.

None of the procedures described above provide a technique for forming arapidly dissolving dosage unit which can be manufactured, shipped andsold to consumers. It is, therefore, an object of the present inventionto provide a method for preparing such a dosage unit.

Other and further objects will be realized by those skilled in the artin view of the following disclosure.

SUMMARY OF THE INVENTION

The present invention is a method of preparing a rapid or quick dissolvecomestible unit by mixing uncured shearform matrix and an additive,molding the mixture to form a unit dosage form, and curing the shearformmatrix. Preferably, the shearform matrix includes a crystallizationenhancer and/or a binding aid.

The shearform matrix used to form dosage units in accordance with theinvention can be made with flavors and/or sweeteners included in thefeedstock used to make the matrix. Flavors can be chosen from naturaland synthetic flavoring liquids. Sweeteners are those materials whichprovide sweetness to the matrix in addition to sweetness which isprovided by the carrier material used to form the matrix, e.g., sucrose.

The mixture can be molded by being introduced in a unit dosage well andtamping the mixture therein. The tamped mixture is then cured by beingsubjected to environmental conditions of heat, moisture, and pressurewhich induce crystallization. For example, the unit can be cured byincreasing the heat under substantially constant moisture condition. Theheat can be increased by subjecting the tamped unit to microwave energy.

The additive, of course, is preferably an active ingredient such as amedicament.

Another type of additive which can be used in the present invention isan effervescent disintegration agent. The term effervescentdisintegration agent(s) includes compounds which evolve gas. Thepreferred effervescent agents evolve gas by means of chemical reactionswhich take place upon exposure of the effervescent disintegration agentto saliva in the mouth. The agent or agents can be included in severalways in the units of the present invention. First of all the agents canbe incorporated in the matrix by mixing with the feedstock prior toflash flow processing. Alternatively, the entire effervescent agent canbe mixed with the shearform matrix after it has been produced by flashflow techniques. As yet a third alternative, one part of the agent canbe included in the feedstock which is flash flow processed while theother part of the agent can be incorporated after flash flow processing.In any event, the effervescent disintegration agent provides forcontrolled and rapid disintegration of the tablet when placed in themouth and provides for a positive organoleptic sensation by theeffervescent action in the mouth. The texture, speed and sensation ofdisintegration can especially be adapted for use by children incombination with taking one or more of the medicaments contemplated foruse in the present invention.

"Tamping" is used herein to mean that the mixture is subjected tocompression pressure of less than about 500 lbs. per sq. in. (psi),preferably less than 250 psi, and most preferably from about 20 to about100 psi.

Another method of identifying the compression force required to molduncured matrix in accordance with the present invention is byidentifying the density resulting from tamping. The product of thepresent invention should be compressed in its uncured condition to adensity of not greater than about 1.2, preferably not greater than about0.8, and most preferably not greater than about 0.65. In one mostpreferred embodiment, the density of the finished product is between0.25 and 0.40.

The product prepared in accordance with the method set forth above candissolve in the mouth of the consumer in less than 10 seconds. Usually,well made product produced in accordance with this process will dissolvewithin less than 5 seconds, and, most preferably less than 3 seconds.The most highly dissoluble units have been described as literally"exploding" in the mouth.

The present invention also includes a composition for delivering anactive ingredient which includes the active ingredient incorporated in amolded saccharide-based crystalline structure. The composition alsoincludes the saccharide-based structure which has a bi-dimensionallystabilized crystalline sugar. The sugar is produced by forming a sugarcrystalline frame from an outer portion of an amorphous shearform sugarmass, and subsequently converting the remaining portion of the mass to asubstantially completely crystalline structure. The product ispreferably monodispersed and is also preferably microcrystalline. Fordefinitions relating to monodispersed and microcrystalline as well asother definitions relating to the composition aspects of the presentinvention, reference is made to U.S. Pat. No. 5,597,416, which isincorporated herein by reference. The shearform mass can also include anadditive which is co-crystallized in a crystalline product. Theamorphous shearform mass is substantially rod-shaped, and has twodimensions lying in a cross-sectional plane of the rod. The singledimension extends along a linear axis of the rod. Preferably, themonodispersed structurally stabilized cross-section does not exceed 50μm, and preferably does not exceed 10 μm.

Another embodiment of the present invention is an apparatus whichimplements the mixing and filling procedure, tamping, and curing in acontinuous manufacturing process. The elements of the apparatus includea filler, tamper, and curing station. Preferred embodiments of theinventive apparatus include a mixer adjacent to, or in combination with,the filling station.

In another preferred embodiment, the apparatus also has a packagingcapability. This can include a continuous feed package substrate and aforming station which provides the tamping wells which are subsequentlyfilled with the mixed shearform product and additive. And, in yet afurther preferred embodiment, the apparatus can include a sealer whichseals the packaged end product followed by a station which separates thecontinuous packaging wells by, for example, a die punch. The entireapparatus can be followed in line by a carton filling station forpreparing cartons and loads, such as palletized loads, for shipment.

Yet another manifestation of the present invention is a method ofadministering an active ingredient to a human host. The method includesingesting a quick dissolve comestible unit prepared by the method of thepresent invention, i.e., mixing uncured shearform matrix and an activeingredient, followed by molding a unit dosage and curing the shearformmatrix in the unit dosage form. The next step requires the host toretain the quick dissolve unit in the oral cavity for a time sufficientto contact the unit with water while in the oral cavity. Finally, thehuman host introduces water to the oral cavity while the unit isretained therein to enhance dissolution of the dosage unit.

As a result of the process and apparatus described herein, a rapidlydissolving dosage unit can be manufactured on a continuous basis andeven prepared for shipment to the consumer in a single manufacturingline. The product can be made to provide the stunning sensation ofexploding in the oral cavity upon ingestion by the consumer.

These and other advantages of the present invention will be appreciatedfrom the detailed description and examples which are set forth herein.This description and the examples are set forth to enhance theunderstanding of the invention, but are not intended in any way to limitthe scope thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the invention have been chosen for purposes ofillustration and description, but are not intended in any way torestrict the scope of the present invention. The preferred embodimentsof certain aspects of the invention are shown in the accompanyingdrawings, wherein:

FIG. 1 is a block diagram of the process and apparatus of the presentinvention; and

FIG. 2 is a schematic of a preferred embodiment of a process andapparatus in accordance with the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes a method of making quick dissolvecomestible units, e.g., tablets. The units produced in accordance withthe present invention have the capability of dissolving instantaneouslyin the mouth of the consumer. However, tablets can be produced,packaged, and distributed for sales without deteriorating during anyprocess step along the way. In the past, tablets have been madeprimarily by compressing feedstock under high pressure in order toprovide the necessary hardness for packaging and distribution.Consequently, prior art tablets so produced are limited in that they arenot rapidly-dissoluble in the mouth. High density packing resulting fromhigh compression tabletting hinders disintegration and wetting theinterior portion of the tablet. This aspect of the prior art has beenimproved by the technology disclosed in parent U.S. application Ser. No.194,682, filed on Feb. 10, 1994.

As a result of the present invention, however, a profound step forwardhas been made in the art of preparing dosage units which are intended todissolve in the mouth. The tablets produced by the present inventiondissolve within seconds. The product is prepared by a unique combinationof processing steps. The invention also includes apparatus for makingthe tablets as well as the tablets (or dosage units) themselves.

The first step of the procedure is to mix an uncured shearform matrixand an additive, such as an active ingredient, to prepare for molding aunit dosage. "Shearform matrix" in the present invention means a matrixproduced by subjecting a feedstock which contains a carrier material toflash flow processing.

Flash flow processing can be accomplished several ways. Flash-heat andflash-shear are two processes which can be used. In the flash-heatprocess the feedstock material is heated sufficiently to create aninternal flow condition which permits part of the feedstock to move atsubparticle level with respect to the rest of the mass and exit openingsprovided in the perimeter of a spinning head. The centrifugal forcecreated in the spinning head flings the flowing feedstock materialoutwardly from the head so that it reforms with a changed structure. Theforce necessary to separate and discharge flowable feedstock iscentrifugal force which is produced by the spinning head.

One preferred apparatus for implementing a flash heat process is a"cotton candy" fabricating type of machine. The spinning machine used toachieve a flash-heat condition is a cotton candy machine such as theEcono-Floss Model 3017 manufactured by Gold Medal Products Company ofCincinnati, Ohio. Any other apparatus or physical process which providessimilar forces and temperature gradient conditions can also be used.

In the flash-shear process, a shearform matrix is formed by raising thetemperature in the feedstock material which includes a non-solubilizedcarrier, such as a saccharide-based material until the carrier undergoesinternal flow upon application of a fluid shear force. The feedstock isadvanced and ejected while in internal flow condition, and subjected todisruptive fluid shear force to form multiple parts or masses which havea morphology different from that of the original feedstock.

The multiple masses are cooled substantially immediately after contactwith the fluid shear force and are permitted to continue in a free-flowcondition until solidified.

The flash shear process can be carried out in an apparatus which hasmeans for increasing the temperature of a non-solubilized feedstock andmeans for simultaneously advancing it for ejection. A multiple heatingzone twin screw extruder can be used for increasing the temperature ofthe non-solubilized feedstock. A second element of the apparatus is anejector which provides the feedstock in a condition for shearing. Theejector is in fluid communication with the means for increasing thetemperature and is arranged at a point to receive the feedstock while itis in internal flow condition. The ejector is preferably a nozzle whichprovides high pressure ejection of the feedstock material. Seeco-pending commonly-owned U.S. patent application Ser. No. 965,804 filedOct. 23, 1992 entitled "Process For Making Shearform Matrix," now U.S.Pat. No. 5,380,473 which is incorporated herein by reference.

The feedstock for producing shearform matrix includes a carriermaterial. The carrier material can be selected from material which iscapable of undergoing both physical and/or chemical changes associatedwith flash-flow processing. Materials useful as matrices may be chosenfrom those carbohydrates which are capable of forming free-formagglomerates upon being processed.

Preferred materials useful as matrices may be chosen from such classesas "sugars". "Sugars" are those substances which are based on simplecrystalline mono- and di-saccharide structures, i.e., based on C₅ and C₆sugar structures. "Sugars" include sucrose, fructose, lactose, maltose,and sugar alcohols such as sorbitol, mannitol, maltitol, etc. Thepreferred choice of sugar in the present invention is sucrose.

Preferred combinations of sugars includes sugars as used herein incombination with other mono-, di-, tri-, and polysaccharides up to 50%of the total amount, preferably up to 30% and most preferably up to 20%.

A shearform product is used in the technique of the present invention toobtain the new sugar product. A shearform sugar product is asubstantially amorphous sugar which results from subjecting sugar toheat and shear sufficient to transform crystalline (usually granulated)sugar to amorphous sugar without the use of a solution. Thus, in thesense of the present invention, a shearform sugar product ischaracterized as a sugar product resulting from a non-solubilized sugar.It is the starting material for forming the unique crystalline productof the present invention.

Other carrier materials can be used, but preferably in combination withsugar--not as a total replacement.

Maltodextrins are an example of other carrier materials. Maltodextrinsinclude those mixtures of carbohydrates resulting from hydrolysis of asaccharide feedstock which are described as solids having a DE of up toand including 65.

The feedstock can also include maltooligosaccharides produced byselective hydrolysis of cornstarch followed by removal of high and lowmolecular weight compounds. The general description ofmaltooligosaccharides as contemplated herein is set forth in co-pendingU.S. application Ser. No. 07/847,595 filed Mar. 5, 1992, U.S. Pat. No.5,387,431.

Polydextrose is also contemplated for use as a carrier. Polydextrose isa non-sucrose, essentially non-nutritive carbohydrate substitute. It canbe prepared through polymerization of glucose in the presence ofpolycarboxylic acid catalyst and polyols. Generally, polydextrose isknown to be commercially available in three forms: polydextrose A andpolydextrose K, which are powdered solids, and polydextrose N suppliedas a 70% solution. Each of these products also contain some lowmolecular weight components, such as glucose, sorbitol and certainoligomers. Regarding polydextrose, Applicants incorporate herein thecontents of co-pending, U.S. application Ser. No. 07/881,612 filed May12, 1992, abandoned.

As previously mentioned, each of the carriers are used primarily incombination with sugars, and not as a total replacement.

Other materials which can be incorporated into the feedstock to enhancethe shearform matrix include flavors and sweeteners (other than thecarrier itself).

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationthereof. A non-limiting representative list of examples includes citrusoils such as lemon, orange, grape, lime and grapefruit and fruitessences including apple, pear, peach, grape, strawberry, raspberry,cherry, plum, pineapple, apricot or other fruit flavors.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral, i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime) decanal (orange, lemon), aldehydeC-8 (citrus fruits), aldehyde C-9 (citrus fruits), adlehyde C-12 (citrusfruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (greenfruit), and 2-dodecenal (citrus, mandarin), mixtures thereof and thelike.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and mixturesthereof (when not used as a carrier); saccharin and its various saltssuch as the sodium salt; dipeptide sweeteners such as aspartame;dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside);chloro derivatives of sucrose such as sucralose; sugar alcohols such assorbitol, mannitol, xylitol, and the like. Also contemplated arehydrogenated starch hydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof. Other sweeteners may also be used.

Yet a further embodiment of the present invention includes the use of aneffervescent disintegration agent. Its action can aid in the masking ofobjectionable taste of active ingredients such as vitamins, medicinesand/or minerals, etc. It is generally believed that the positiveorganoleptic sensation achieved by the effervescent action in the mouth,the texture, speed and sensation of disintegration aids in maskingundesirable flavor notes in the mouth.

In preferred embodiments of the present invention, the effervescentdisintegration agent may include at least one acid selected from thegroup consisting of citric acid, tartaric acid, malic acid, fumaricacid, adipic acid, succinic acid, acid anhydrides and acid salts andmixtures thereof, and at least one base selected from the groupconsisting of carbonate salts, bicarbonate salts and mixtures thereof.

Inasmuch as the term effervescent refers to those agents which evolvegas, the bubble or gas generating the action is most often the result ofthe reaction of a soluble acid source and an alkali metal carbonate orcarbonate source. The reaction of these two general classes of compoundsproduces carbon dioxide gas upon contact with water included in saliva.Carbonate sources include dry solid carbonate and bicarbonate salts suchas sodium bicarbonate, sodium carbonate, potassium bicarbonate andpotassium carbonate, magnesium carbonate and sodium sesequicarbonate,sodium glycine carbonate, L-lysine carbonate, arginine carbonate andamorphous calcium carbonate. While the food acids can be those indicatedabove, acid anhydrides of the above-described acids may also be used.Acid salts may include sodium, dihydrogen phosphate, disodium dihydrogenpyrophosphate, acid citrate salts and sodium acid sulfite. Other sourceof effervescence can be included and the present invention is notlimited to those specifically set forth herein.

Also as previously mentioned, the ingredients of the effervescent agentcan be included in one of at least three different ways. The firstmethod includes incorporating the entire effervescent agent in thefeedstock which is used to form the shearform product. The second mannerof incorporating an effervescent disintegrating agent is to include theentire agent as an additive which is mixed with shearform matrix afterit is formed. The third method contemplates incorporating one portion ofthe disintegrating agent in the shearform matrix and another portion ofthe disintegrating agent as an additive after formation of the shearformmatrix material. The artisan will determine the best way to preserve theagent for its disintegrative and effervescent properties upon ingestionby the host.

The shearform matrix used in the inventive process must be uncuredbefore it is molded. "Uncured" means amorphous or having a degree ofamorphousness which enables the formation of a dosage unit upon curing."Curing" means transforming the matrix from amorphous to crystallinewhile being sufficiently bound to produce a stable structure.

Curing can be enhanced by crystallization modifiers. Crystallizationmodifiers can be added to the feedstock before flash flow processing,such modifiers include, but are not limited to, surfactants (Spans™ andTweens™), dextrose, polyethylene glycol (PEG), polypropylene glycol(PPG), etc. These modifiers generally provide controlled acceleration ofcrystallization while the matrix is bound.

Crystallization modifiers enhance the formation of a crystalline frameand the conversion of the remaining mass. Enhancement as used withrespect to the process of the present invention principally meansacceleration of the process. Enhancement also includes contribution tothe strength of the crystalline structure, and predictability ofresults. Other benefits such as reduced-size product also is achieved byuse of crystallization modifiers.

Crystallization modifiers, which are preferably added to sugars beforebeing processed to amorphous shearform mass (or can be coated on thesugar), are used to affect the rate of crystallization. Water itself isa crystallization modifier, and is preferably included in the amorphousshearform sugar mass in an amount of between about 0.5% to about 2.0%.Non-saccharide hydrophilic organic materials (NSHMs) are also used ascrystallization modifiers. Even though some NSHMs are surfactants, othermaterials can be used. Materials found to be most effective have ahydrophilic to lipid balance (HLB) of 6 or greater, i.e., they have thesame degree of hydrophilicity as surfactants characterized by degree ofHLB. Such materials include, but are not limited to anionic, cationic,zwitterionic surfactants as well as neutral materials which have an HLBof six (6) or greater. Preferred NSHMs are hydrophilic materials havingpolyethylene oxide linkages. Also, the preferred NSHM's have a molecularweight of at least 200 and preferably at least 400.

Lecithin is one surface active agent for use in the present invention.Lecithin can be included in the feedstock in an amount of from about0.25 to about 2.00% by weight. Other surface active agents include, butare not limited to, the Spans™ and Tweens™ which are commerciallyavailable from ICI Americas Inc. Carbowax™ is yet anothercrystallization modifier which is very useful in the present invention.Preferably, Tweens™ or combinations of surface active agents are used toachieve the desired HLB.

By use of a surfactant the process and product of the present inventioncan be reproduced with a high degree of predictability. As additionalcrystallization modifiers which enhance the procedure and product of thepresent invention are identified, Applicants intend to include all suchadditional crystallization modifiers within the scope of the inventionclaimed herein.

The process of the present invention requires mixing an additive withthe uncured shearform matrix. When the shearform matrix is in the formof a floss, it is preferably chopped first to reduce the volume of theproduct without compressing it. The additive can be any ingredient oringredients needed to supply the dosage unit with the requiredcharacteristics. The primary ingredients are medicinal substances.

Medicinal substances which can be used in the present invention arevaried. A non-limiting list of such substances is as follows:antitussives, antihistamines, decongestants, alkaloids, mineralsupplements, laxatives, vitamins, antacids, ion exchange resins,anti-cholesterolemics, anti-lipid agents, antiarrhythmics, antipyretics,analgesics, appetite suppressants, expectorants, anti-anxiety agents,anti-ulcer agents, anti-inflammatory substances, coronary dilators,cerebral dilators, peripheral vasodilators, anti-infectives,psycho-tropics, antimanics, stimulants, gastrointestinal agents,sedatives, antidiarrheal preparations, anti-anginal drugs,vasodialators, anti-hypertensive drugs, vasoconstrictors, migrainetreatments, antibiotics, tranquilizers, anti-psychotics, antitumordrugs, anticoagulants, antithrombotic drugs, hypnotics, anti-emetics,anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- andhypoglycemic agents, thyroid and antithyroid preparations, diuretics,antispasmodics, uterine relaxants, mineral and nutritional additives,antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics,cough suppressants, mucolytics, anti-uricemic drugs and mixturesthereof.

Especially preferred active ingredients contemplated for use in thepresent invention are antacids, H₂ -antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide. Moreover, antacids can be used in combination withH₂ -antagonists.

Analgesics include aspirin, acetaminophen, and acetaminophen pluscaffeine.

Other preferred drugs for other preferred active ingredients for use inthe present invention include antadiarrheals such as immodium AD,antihistamines, antitussives, decongestants, vitamins, and breathfresheners. Also contemplated for use herein are anxiolytics such asXanax; antipsychotics such as clozaril and Haldol; non-steroidalanti-inflammatories (NSAID's) such as Voltaren and Lodine;antihistamines such as Seldane, Hismanal, Relafen, and Tavist;antiemetics such as Kytril and Cesamet; bronchodilators such asBentolin, Proventil; antidepressants such as Prozac, Zoloft, and Paxil;antimigraines such as Imigran, ACE-inhibitors such as Vasotec, Capotenand Zestril; Anti-Alzheimers agents, such as Nicergoline; and Ca^(H)-Antagonists such as Procardia, Adalat, and Calan.

The popular H₂ -antagonists which are contemplated for use in thepresent invention include cimetidine, ranitidine hydrochloride,famotidine, nizatidine, ebrotidine, mifentidine, roxatidine, pisatidineand aceroxatidine.

Other ingredients which may be included are fragrances, dyes, sweetenersboth artificial and natural, and other additives.

For example, fillers may be used to increase the bulk of the tablet.Some of the commonly used fillers are calcium sulfate, both di- and tribasic, starch, calcium carbonate, microcrystalline cellulose, modifiedstarches, lactose, sucrose, mannitol, and sorbitol.

Other ingredients includes binders which contributes to the ease offormation and general quality of the tablet. Binders include starches,pregelatinize starches, gelatin, polyvinylpyrrolidone, methylcellulose,sodium carboxymethylcellulose, ethylcellulose, polyacrylamides,polyvinyloxoazolidone, and polyvinylalcohols.

Lubricants can also be used to aid in tamping and compacting. Lubricantscan include, but are not limited to, the following: magnesium stearate,calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex,polyoxyethylene, monostearate, talc, polyethyleneglycol, sodiumbenzoate, sodium lauryl sulfate, magnesium lauryl sulfate and lightmineral oil.

Furthermore, disintegrants can be used to enhance the dispersibility ofthe compressed tablet in an aqueous environment. The dispersants caninclude starch, alginic acid, guar gum, kaolin, bentonite, purified woodcellulose, sodium starch glycolate, isoamorphous silicate, andmicrocrystalline cellulose. In view of the highly dissoluble nature ofthe product of the present invention, there is little need fordisintegrants.

Another ingredient useful in tabletting are glidants which adhere to thecohesive material in order to enhance flow properties by reducinginterparticle friction. Glidants which can be used include starch, talc,magnesium and calcium stearate, zinc stearate, dibasic calciumphosphate, magnesium carbonate, magnesium oxide, calcium silicate, andsilica aerogels.

Color additives useful in preparing tablets include food, drug andcosmetics (FD&C) colors, drug and cosmetic (D&C) colors, or externaldrug and cosmetic (Ext. D&C) colors. These colors are dyes, theircorresponding lakes, and certain natural and derived colorants. Lakesare dyes absorbed on aluminum hydroxide.

In a preferred embodiment, the present invention is particularly usefulin preparing antacid tablets. Antacids are conveniently provided inchewable tablet form to provide a convenient method of deliveringantacid to the consumer. The chewable form provides an advantage in thatthe tablet is broken up into granules during chewing and mixed withsaliva before swallowing. This renders the tablet antacid formulation asuspension. One of the disadvantages of prior art antacid tablets isthat the mass of ingredients residing in the mouth during and afterchewing have objectional texture and taste. The present inventionovercomes these disadvantages because the ingredients virtually explodeinto dissolution. The texture is also significantly enhanced and theresidence time is substantially reduced.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, calcium carbonate,calcium phosphate, citrate ion (acid or salt), amino acetic acid,hydrate magnesium aluminate sulfate, magaldrate, magnesiumaluminosilicate, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, magnesium oxide, magnesium trisilicate, milksolids, aluminum mono-ordibasic calcium phosphate, tricalcium phosphate,potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesiumaluminosilicates, tartaric acids and salts.

After the ingredients of the "additive" have been mixed with the uncuredshearform matrix, the result of mixture must be "molded" as a unitdosage form.

"Molding" is used herein to mean associating uncured (i.e.,uncrystallized) shearform matrix material closely enough to providebridging between crystallized matrix material upon curing. Generally,this requires force sufficient to provide intimate contact of fibersprior to curing, followed by crystallizing to form a bound continuouscrystalline structure throughout the tablet. Unlike conventionaltabletting which relies primarily on compression to provide thestructure, the present process utilizes the curing process to aid informing the end product. Consequently, mild compression forces can beused to mold the product. In a preferred embodiment, the compressionrequired to mold uncured matrix material is referred to as "tamping."

"Tamping" means compressing with force less than that required incompression tabletting, which is generally regarding as being on theorder of thousands of pounds per square inch (psi). The maximum pressureused in the present invention is only 500 psi, but in most cases willnever exceed about 250 psi, and, in the most preferred embodiments, notmore than 80 psi (e.g., 40 psi to 80 psi). These lower pressures arecalled tamping.

Another method of measuring the compression force required to "mold"uncured matrix is by product density. The product of the presentinvention should be compressed in an uncured condition to a density ofnot greater than about 1.20, preferably not greater than 0.8, and, mostpreferably, not greater than 0.65.

Inasmuch as the present invention requires extremely low pressures formolding, it is possible to mold directly in plastic product wells whichcan be used as packaging for sales. Consequently, the present inventionincludes the concept of molding uncured matrix materials clearly inproduct wells such as plastic blister package depressions.

After preparing shearform matrix and molding the uncured matrix, theproduct must be cured. Curing means binding and crystallizing the matrixmaterial substantially simultaneously. Curing is performed by subjectingproduct to heat and moisture sufficient to provide controlledcrystallization. Controlled crystallization occurs when points ofcontact of uncured matrix material become points of crystalline growthand crystallization of the material proceeds to provide crystallinestructures. Binding occurs at the points of contact, and thesimultaneous crystalline growth is such as to maintain structuralintegrity.

The "curing" process of the present invention involves a transformationfrom amorphous to crystalline state. The transformation must take placewhile the amorphous shearform matrix remains bound together.

Moreover, curing requires the transformation to take place withoutcollapsing the structural integrity of the matrix in its "formed"condition. Since amorphous shearform product is hygroscopic, thistransformation can be difficult. When points of contact between piecesof matrix can be made points of crystalline growth during curing,structural integrity is established and maintained. One way of promotingthe occurrence of this phenomenon is to include crystallizationenhancers, e.g., surfactants, any alcohol, polyethylene glycol,polypropylene glycol, etc. Without being bound by theory, it is believedcontrol of the propagation of crystalline growth as outlined above isimproved significantly by use of crystallization enhancers.

Prior to curing, the mixture of shearform matrix and active aremaintained at temperature and humidity below the glass transitiontemperature of the shearform matrix material.

Conditions suitable for curing can include ambient conditions of heatand moisture or modified ambient conditions. For example, it has beenfound that curing can be conducted at a temperature of 0°-90° C. at arelative humidity of 25-90%. In one case, it has been found that curingwill take place within 15 minutes at 40° C. and 85% r.h. In other cases,optimum temperature range has ben found to be at 20°-50° C. Microwaveenergy can be used to controlledly accelerate curing.

Generally, the crystallization is effected in an environment wherein thetabletted material cures to a water content of less than 5% by weight,and preferably less than 1% by weight based on the weight of the tablet.Thus, the curing environment, e.g., chamber or room, is maintained at arelative humidity which permits water pickup no greater than 5%, andpreferably less than 1%.

It has been found that curing product in a package well results inshrinkage of the tablet from the walls of the well. This feature isparticularly advantageous for purposes of manufacturing individualdosage units since molding and curing can be performed in the packageused for commercial sales. Consequently, several transfer steps can beeliminated.

Products prepared in accordance with the present invention have beenfound to have densities of from about 0.20 gm/cc² to about 0.90 gm/cc²,and some preferred embodiments have densities of from about 0.40 gm/cc²to about 0.65 gm/cc².

Another ingredient which can be included in the shearform matrix is abinding aid or agent. A binding agent is used to assist in the moldingstep and, in some cases, contributes to the dissolution capabilities ofthe finished product. Binding agents useful herein includelow-glass-transition materials. Some agents found useful include, butare not limited to, sorbitol, mannitol, lactose, etc. The binding agentsare flash flow processed with the carrier. Binding agents also aid inholding the matrix material in place for curing. In some cases portionsof the binder becomes part of the matrix material.

Referring to FIG. 1, a schematic of the process and apparatus inaccordance with the present invention is shown. In particular, a mixingstation 10 is shown in combination with a formation station 12 and acuring station 14, which are located in series and downstream of themixing station 10. The mixing station 10 can receive feedstock from asource of shearform product 22. The source of shearform product can beflash flow process apparatus such as those been previously describedherein. The source of shearform product can also include weighingapparatus. Premixing apparatus can also include a macerating (orchopping) station 22, in which shearform product in the form of flosscan be chopped.

The mixing station 10 can also receive additive material from a station30. The station 30 can also include weighing and mixing apparatus sothat the additive can be properly prepared before it is mixed with theshearform product in station 10.

In forming station 12, dosage units are formed by tamping. The dosageunits formed in station 12 are then transferred to curing station 14which can include heat, pressure and moisture control means forproviding the type of curing desired.

Optionally, the process of the present invention can also include apackaging station 40.

In order to demonstrate a preferred form of the invention, reference ismade to FIG. 2. In FIG. 2, an in-line apparatus and schematic process isdepicted wherein plastic stock material can be continuously providedfrom stock roll 9. Plastic stock can then be formed into a continuoustray having product wells 6 by vacuum forming at vacuum forming station8. Each of the wells 6 can be filled at fill and forming station 11.

Fill and forming station 11 in FIG. 2 includes stations 10 and 12 of theschematic process shown in FIG. 1. That is to say, both the shearformproduct and an additive can be mixed, delivered to each of the wells 6,and formed by tamping at station 11 shown in FIG. 2. Proceeding alongthe process of FIG. 2, the product can then be cured at curing station13.

Lid stock, such as continuous sheet material can be fed from a stockroll 41, and joined in a secure fashion (such as by adhesion) to the topof the continuous plastic tray material 9 thereby sealing product wells6.

In order to obtain unit packaging suitable for sales to individualcustomers, the continuous sheet can then be separated into customer sizelengths by a die punch 43. Finally, the customer size packages can thenbe boxed in a carton at a packing station 45. The cartons can then beloaded for shipment as, for example, in a palletized configuration.

The present invention has been found to be ideally suited forpreparation of antacid tablets and tablets in which antacids are used asan ingredient to ameliorate the acid conditions in the body in order toassist drugs which do not tolerate acidic conditions. In the case ofantacids themselves, the instantaneous dispersion of the tablet in themouth prevents the residual chalky taste of a conventional antacidtablet. In the case of ingredients which do not tolerate acidicconditions, it is desirable to include the antacids plus the"acid-sensitive" pharmaceutical in a dosage unit prepared according tothe invention. For example, didanosine is an antiviral agent which doesnot tolerate an acidic environment well. Consequently, the use ofdidanosine in combination with an antacid such as calcium carbonate inthe same drug delivery system is an ideal method of introducing the drugto the body. The present invention includes the combination of an"acid-sensitive" ingredient and an antacid in a dosage unit.

Actual tests have been conduced to show the efficacy of the presentinvention. These examples have been set forth herein for the purpose ofillustration and demonstration. The scope of the invention, however, isnot to be in any way limited by the examples.

The shearform matrix material used in the following examples is anamorphous sugar. Amorphous sugar as used herein means a sugar stockwhich contains a high percentage of amorphism, i.e., greater than 50% byweight, and preferably greater than 70% by weight of the sugar stock isamorphous.

In all examples the shearform matrix was analyzed by both DifferentialScanning Calorimetry (DSC) and polarized light under a microscope. Ineach case the shearform matrix was formed to be substantially amorphousbefore the active ingredient was added.

EXAMPLES ANTACID EXAMPLE

A shearform matrix was prepared for use in the process of the presentinvention. The matrix was prepared by subjecting a blend of appropriateingredients and subjecting to flash flow processing in a cotton candytype apparatus. The combination included the saccharide-based carriermaterial sucrose, sorbitol as a binding agent, and a surfactant known asTween™ 60 provided by ICI. The blend was provided according to theformula set forth below in the Shearform Matrix Table 1.

                  TABLE 1    ______________________________________    SHEARFORM MATRIX TABLE 1                      Amount    Ingredient        By Weight   Percentage    ______________________________________    Sugar (Sucrose)    84.75 g     84.75%    Binding Agent      15.00 g     15.00%    (Sorbitol)    Surfactant (Tween ™ 60)                       0.25 g      0.25%    Totals            100.00 g    100.00%    ______________________________________

The sorbitol, sucrose and surfactant were mixed by hand, thenmechanically in a mixing apparatus. The resulting mixture was introducedto an Econo Floss™ machine and flash flow processed at approximately3,600. The shearform matrix resulting from the processing was an uncuredwhite floss which was reduced in volume by chopping.

After preparation of the shearform matrix, an additive was mixed withuncured matrix material. The total combination is set forth below in theUnit Dosage Table 2.

    ______________________________________    UNIT DOSAGE TABLE 2    Ingredient             Percentage    ______________________________________    Shearform Matrix (Floss From Table 2)                           46.70%    Calcium Carbonate (CaCO.sub.3)                           50.00%    High Intensity Sweetener (Aspartame ™)                           0.30%    Flavoring              2.50%    Polyethylene Glycol (PEG 300)                           0.50%                           100.00%    ______________________________________

The ingredients set forth above were mixed in order to prepare forforming and curing. The mixture resulting from Unit Dosage Table 2 wasweighed out in 0.75 g samples and introduced to molds approximately 0.75inches in diameter. Tablets were formed by tamping the ingredients atpressures of both 60 psi and 80 psi. The formed tablets were cured in anoven at 40° C. and 85% relative humidity for approximately 15 minutes.

The resulting tablets were very attractive looking having a smooth andshiny surface. The tablets were also prepared in a smaller mold having adiameter of about 0.65 inches. Similarly, the smaller tablets weremolded at 60 psi and 80 psi and cured in accordance with the procedureset forth above. The resulting product also had an attractive appearancewith a smooth and shiny surface.

The tablets resulting from this procedure were very fast melt. They didnot have a chalky mouthfeel during consumption. The taste was excellent.

Antacid Example 2

The procedures set forth above was repeated with a different antacidformulation. The new formulation also used the chopped or maceratedfloss prepared in accordance with Shearform Matrix Table 1. The newformulation is set forth in Unit Dosage Table 3.

    ______________________________________    UNIT DOSAGE TABLE 3    Ingredient             Percentage    ______________________________________    Shearform Matrix (Floss From Table 1)                           46.20%    Calcium Carbonate (CaCO.sub.3)                           50.00%    High Intensity Artificial Sweetener                           0.30%    (Aspartame ™)    Flavoring              2.50%    Polyethylene Glycol (PEG 300)                           0.50%    Dye (Red FD&C No. 40)  0.50%                           100.00%    ______________________________________

Tablets were made similarly to the process set forth with regard to UnitDosage Formula 2, both with large and smaller molds and at both 60 psiand 80 psi. The color tablets produced in accordance with the third unitdosage formula were similar to those produced with the first formula.The tablets made with the third formula were very quick dissolving andthey had a smooth and shiny surface. After four days, the tablets hadset. They did not manifest a chalky mouthfeel when consumed. The tabletsretained structural stability while in the product wells.

Tablets prepared in accordance with Formula 2 and Formula 3 hadsufficient hardness for subsequent handling and distribution toconsumers.

IBUPROFEN EXAMPLE

A shearform matrix material was prepared in accordance with the formulaset forth in Shearform Matrix Table 4.

    ______________________________________    SHEARFORM MATRIX TABLE 4    Ingredient         Percentage    ______________________________________    Sugar (Sucrose)    84.75%    Binding Agent (Sorbitol)                       12.00%    Binding Agent (α Lactose)                       3.00%    Surfactant (Tween ™ 80)                       0.25%    Total              100.00%    ______________________________________

The sucrose, sorbitol and lactose were mixed first by hand and then bymachine until a homogenous blend was produced. To this mixture, thesurfactant was added and mixed by hand. The blend was then subjected toflash flow processing in a Econo Floss Machine No. 7025 at approximately3,600 rpm at a temperature setting of high. The spun material wascollected as a floss and macerated in a mixing machine for about 45seconds. The resulting material was a reduced volume shearform matrix inuncured condition.

An ibuprofen mixture was prepared in accordance with the presentinvention in accordance with the formula set forth below in IbuprofenTable 5.

    ______________________________________    IBUPROFEN TABLE 5                      Amount    Ingredient        By Weight   Percentage    ______________________________________    Shearform Matrix (Floss                      54.41 g      60.46%    From Table 4)    Ibuprofen (Microcaps)                      28.88 g      32.09%    Flavor             5.40 g      6.00%    High Intensity Artificial                       0.72 g      0.80%    Sweetener (Aspartame ™)    Lecithin (Yelkin DS)                       0.32 g      0.35%    Silica (Syloid 244)                       0.23 g      0.25%    Orange Color       0.05 g      0.05%    Totals            90.01 g     100.00%    ______________________________________

The lecithin and ibuprofen was mixed and added to the ground flossmaterial. The ingredients were mixed in a mechanical mixing apparatusfor 15-20 seconds. The flavors, high intensity sweetener, syloid werethen added and mechanically mixed with an additional 10-15 seconds.Finally, the color was added and mixed until the blend took on ahomogenous orange color.

The ingredients mixed well on a large scale. The mixture had ahomogenous density and excellent flow characteristics. The mixture wasadded in portions of 0.75 grams to a die having a 0.65 inch diameter.The ingredients were then tamped at a pressure of 80 psi.

The tamped dosage units were then cured. Some of the tablets were curedfor one day at room temperature and then the packages were sealed fortesting at a later date.

In general, the tablets resulting after curing were smooth and easy tohandle without disintegration of the tablet units. Moreover, the tabletsdispersed quickly in the mouth and produced little or no unwanted mouthfeel.

The ibuprofen product included highly desirable unit dosages suitablefor consumer ingestion.

ASPIRIN EXAMPLE

A shearform matrix was prepared in accordance with the same formula andprocedure as set forth above with respect to the ibuprofen example. Anaspirin sample formulation was prepared in accordance with the amountsset forth below in Aspirin Table 6.

    ______________________________________    ASPIRIN TABLE 6                      Amount    Ingredient        By Weight   Percentage    ______________________________________    Shearform Matrix (Floss                      17.10 g      62.18%    From Table 4)    Aspirin            9.00 g      32.73%    Flavor             1.00 g      3.64%    High Intensity Artificial                       0.25 g      0.91%    Sweetener (Aspartame ™)    Wetting Agent-Lecithin                       0.10 g      0.36%    (Yelkin DS)    Flow Agent         0.05 g      0.18%    (Syloid 244 FP)    Totals            27.50 g     100.00%    ______________________________________

The aspirin and lecithin were mixed and then added to the choppedshearform matrix. These ingredients were mixed and then the flavors andhigh intensity sweeteners were added and mixing was continued. Finally,the flow agent and colors were added and mixing continued until ahomogenous mixture was obtained.

The blend was introduced to product wells and then tamped at 80 psi toform aspirin containing dosage units. The tablets were then cured bypermitting them to remain at room temperature for approximately one day.These samples were tasted and it was found that the dosage unitsdissolved in the mouth in less than 5 seconds. The flavor was good andthere was no chalky residue or mouthfeel in the oral cavity.

Another aspirin example was prepared in accordance with the table setforth below.

    ______________________________________    ASPIRIN TABLE 7                      Amount    Ingredient        By Weight   Percentage    ______________________________________    Shearform Matrix (Floss                      14.60 g      58.40%    From Table 4)    Aspirin            9.00 g      36.00%    High Intensity Artificiai    Sweetener (Aspartame ™)                       0.25 g      1.00%    Flavor             1.00 g      4.00%    Wetting Agent-Lecithin                       0.10 g      0.40%    (Yelkin DS)    Flow Agent         0.05 g      0.20%    (Syloid 244 FP)    Totals            25.00 g     100.00%    ______________________________________

Twenty tablets were prepared in accordance with the procedure set forthabove with the respect to the first aspirin examples. That is to say,unit dosages were tamped at 80 psi and permitted to cure overnight atroom temperature and humidity. The resulting tablets were attractive andhad a good taste and texture. They melted quite rapidly in the mouth,i.e., generally in less than 5 seconds.

ACETAMINOPHEN EXAMPLE

The floss used in the acetaminophen preparations is the same floss thatwas prepared in accordance with the Shearform Matrix Table 4. A blend ofingredients was prepared in accordance with the formula set forth belowin Acetaminophen Table 8.

    ______________________________________    ACETAMINOPHEN TABLE 8                      Amount    Ingredient        By Weight   Percentage    ______________________________________    Shearform Matrix (Floss                      11.01 g      44.04%    From Table 4)    Acetaminophen     12.19 g      48.76%    Flavor             1.50 g      6.00%    High Intensity Artificial                       0.20 g      0.80%    Sweetener (Aspartame ™g)    Wetting Agent-Lecithin                       0.09 g      0.35%    (Yelkin DS)    Totals            24.99 g     100.00%    ______________________________________

The spun and chopped shearform matrix was mixed with the acetaminophenand lecithin to coat the drug. Additional chopped shearform matrix wasmixed until a homogenous mixture result. The remaining ingredients wereadded and blended until a uniform mixture was obtained.

Samples of 0.90 grams of the tablet mix were introduced into tabletmolds. The tablets were formed by tamping with 60 psi.

Half of the tablets were cured at 40° C. and 80% relative humidity for15 minutes in order to cure. The remaining half of the tablets werepermitted to cure at room temperature for approximately one day.

The tablets produced by both methods of curing resulted in a highquality rapidly dispersible units which had excellent mouthfeel and goodtaste. These products are deemed to be commercially valuable since it isknown that the taste of acetaminophen is quite astringent and unpleasantto the consumer.

Thus, while there had been described what are presently believed to bethe preferred embodiments of the present invention, other and furthermodification and changes can be made thereto without departing from thetrue spirit of the invention. It is intended to include all further andother modifications and changes which come within the true scope of theinvention as set forth in the claims.

What is claimed is:
 1. A molded dosage unit for delivering an activeingredient comprising:an active ingredient in a saccharide-basedcrystalline structure which structure is a shearform mass ofbi-dimensionally continuously bound and stabilized crystalline sugarproduced by:i) forming a sugar crystalline frame from the outer portionsof amorphous shearform sugar masses, ii) adding the active ingredient,iii) molding said masses in a dosage unit, and iv) subsequentlyconverting the remaining portion of said masses to a substantiallycompletely crystalline structure, said active ingredient beingincorporated in said crystalline structure before molding.
 2. The dosageunit of claim 1, wherein said masses are bi-dimensionally monodispersed.3. The dosage unit of claim 1, wherein said shearform masses furthercomprise an additive whereby said additive is co-crystallized in saidcrystalline product.
 4. The dosage unit of claim 2, wherein saidmonodispersed stabilized masses are microcrystalline.
 5. The dosage unitof claim 2, wherein each amorphous shearform mass is substantially rodshaped, said two dimensions lying in a cross-sectional plane of said rodand a third dimension extends along the linear axis of said rod.
 6. Thedosage unit of claim 5, wherein the monodispersed stabilizedcross-section does not exceed 50 μm.
 7. The dosage unit of claim 6,wherein said cross-section does not exceed 10 μm.
 8. A method ofadministering an active ingredient to a human host comprising:ingestinga comestible unit prepared by the method comprising:i) mixing uncuredshearform matrix and an active ingredient, ii) molding a unit dosageform, and iii) curing said shearform matrix; retaining said unit in themouth for a time sufficient to contact said unit with water introducedthereinto; and introducing water into said mouth while said unit isretained whereby dissolution of said unit takes place in the mouth inless than 10 seconds.
 9. A molded dosage unit made from a compositionconsisting essentially of a matrix of rod-shaped crystalline shearformsugar masses, which matrix incorporates an active ingredient, whereinthe active ingredient is incorporated into the matrix by mixing it withuncured shearform matrix, molding into a unit dosage and curing thematrix in the unit dosage form.
 10. The unit dosage of claim 9 in theform of a tablet.